The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”
“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”
“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”
Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.